Anti-TNF, Immunosuppression and Renal Disease: Approaches in TB

Anti-TNF, Immunosuppression and Renal Disease: Approaches

in TB

Dr Heather MilburnConsultant Respiratory Physician

Guy’s & St Thomas’ NHS Foundation TrustREADER IN Respiratory Medicine

KING’S College London

Relative risk of developing active TB(Nice Guidelines, 2006/2011)

Clinical Condition Relative Risk

Diabetes mellitus 2-4

Solid organ transplantation 20-74

Silicosis 30

Chronic renal failure/haemodialysis 10-25.3

Gastrectomy 2.5

Contact smear +ve TB 5-10

HIV 10

Anti-TNF therapy 5

Corticosteroids, MMF, tacrolimus, ciclosporin, aza, mtx, rituximab…..

?

Difficulties in Management of TB & LTBI in Renal Disease

• Risk: ethinic minorities inc risk both TB & CKD

• Screening: when? How? skin anergy; IGRA tests – evaluation.

• Diagnosis: unusual presentations

• Treatment: timing; dosage; drug interactions.

Renal Disease – TB Risk

• Chronic Kidney Disease- Acqu’d i/d state- Functional abnorm N, T&B lympho,

monos, NK cells; vitamin D deficiency- Risk 31.4 in China, ?UK

• Maintenance Haemodialysis- Risk 10-25x (NICE 2006)

• Transplant- Risk 100-400x (Europe & USA; ISC ?higher) - NICE 2006 overall relative risk x37

Incidence of TB - CKD• TB incidence UK 15/100,000; London 44.4/100,000• Dialysis 1,187/100,000 (Moore et al 2002)

0

200

400

600

800

1000

1200

1400

CAPD Haemodialysis FunctioningTransplant

TotalTransplants

General UKPopulation

London

No. ofcases/100,000

Palchaudhuri et al 2011

398

1267

298

522

14.9

44

Uraemic Milieu

neutrophil

Fe overload

Zn deficiency

Intracellular Ca++

Malnutrition – low albumin

Uraemic toxins – guanidines, polyamines

Myeloperoxidase

O2 radicals

bacterial killing

bacterial virulence

Uraemic milieuRenal replacement therapy

IL1b

IL6

TNFa

C’ activation

Chronic inflammation

IL6/IL10 imbalance

Monocyte/APC

IL12

T cell

TH1 TH2

B cell

costimulation

Cellular immune response

Humoral immune response

IFNg

IL4

differentiationIL6

Vit D deficiency

Renal Disease – LTBI & Prophylaxis

• Who?- All uraemic patients?- Only those with particular risk?

• When?- CKD?- On dialysis?- Pre-transplant?- Post-transplant?

• How?- TST?- IGRA?

• What?- 6/12 H- 3/12 RH (drug interactions) - 4-6/12 R (drug interactions)

Renal Disease – Method of Screening

• Pre-transplant• TST – Anergy 30-50%

Drugs – pred, aza, 6-MCP, mtx, cycloph, mycophenolate, ciclosp,

tacrolimus• Interferon-g tests – evaluation?• CXR

Bumbacea et al. Eur Respir J 2012;40:990-1013

IGRAs in ImmunosuppressionCKD

Systematic Review of 30 studies (47):• Predominantly HD• Countries with low-mod TB prevalence• 9 compared IGRAs with TST, 17 TST only, 4 other tests.• cf +ve TST, +ve ELISA more strongly assoc with radiol evidence past TB (OR

4.29, CI 1.83-10.3, p=0.001) and contact with aTB (OR 3.36, CI 1.61-7.01, p=0.001)

• cf –ve TST, -ve ELISA more strongly assoc with BCG (OR 0.30, CI 0.14-0.63, p=0.002)

• Insufficient data to compare ELISPOT with TST or ELISA• ELISA more strongly assoc with risk factors for LTBI in CKD than TST

(Rogerson et al., Am J Kidney Dis 2013)

Study design

Data set consisting of• Mendel Mantoux skin-test• T-SPOT.TB• QuantiFERON-TB Gold In-Tube

Clinical data• TB risk factors• Level of immunosuppression

TBNET

Similar percentages ofpositive test results in all assays

0

10

20

30

40

all<5 years of dialysis>5 years of dialysis

Perc

enta

ge o

f pos

itive

resu

lts

Patients with chronic renal failure

26.3% 26.7%

CRF

27.1%

TBNET

Similar percentages ofpositive test results in all assays

Patients with chronic renal failure

CRF

0

10

20

30

40

all<5 years of dialysis>5 years of dialysis

Perc

enta

ge o

f pos

itive

resu

lts

TBNET

Agreement between the tests

K=0.32

neg pos

neg158 (60.3%)

35 (13.4%)

pos 34 (13.0%)35 (13.4%)

K=0.28

neg pos

neg155 (59.2%)

38 (14.5%)

pos 36 (13.7%) 33 (12.6%)

K=0.52

neg pos

neg167 (63.7%)

25 (9.5%)

pos 24 (9.2%) 46 (17.6%)

CRF

TBNET

No association with TB exposure

crude age, sex, duration of dialysis

OR 95% CI OR 95% CI

1.2 0.6-2.2 1.1 0.6-2.3

1.3 0.7-2.3 1.2 0.6-2.3

1.2 0.6-2.5 1.3 0.6-2.6

CRF

TBNET

BTS Recommendations 2010

• Screening for LTBI - Method:Use IGRA with or without TST

• Who to screen:Pre-transplantContacts

• Chemoprophylaxis:6H if post transplant3RH if pre transplant4R if pre transplant

Drug Recommendations: Chemoprophylaxis

• H & R - normal doses in CKD.

• Long term use of isoniazid is not recommended.

• No evidence for prolonged chemoprophylaxis with any of above.

• No evidence for lower doses - lower peak levels and drug resistance.

Guidelines for management of TB & LTBI in CKD;Thorax 2010:65:559-70

Active TBRoutine Assessment:• History – prev TB, Rx & time, recent contact• Chronic cough, wt loss, sweats – CXR• Sputum, ind sputum, FOB, EBUSPresentation:• Not always classic• Extra pulmonary common – 30-50%; peritonealInvestigation:• Active TB suspected –fluid or tissue for culture & sensitivity testing;

histology• Active pulm disease – isolate in negative pressure room• Notify• INVOLVE CHEST PHYSICIANS

40yr old white MPeritoneal dialysis 1yr

Abdom pain, Cloudy dialysate, No coughT 38, WCC 5.4, N 4.4, Ly 0.8, CXR unremarkableBlood cultures –ve, MC&S of dialysate –veFrom Latvia, UK 1yrAntibiotics 1/52No improvementFurther specimens negChange antibioticsNo improvementAbdo US – nodes and omental thickeningBiopsy – granulomata, no AFB seen, grew H resistant TB

Pharmacokinetics & Toxicity of first-line drugs in CKD

• H: metabolised by liver- neurotoxicity – give pyridoxine- neuropsychiatric disturbance- ototoxicity – rare and can occur in CKD

• R: metabolised by liver- no signif increase tox

• Z: metabolised by liver- uric acid retention – gout

• E: 80% excreted unchanged by kidneys- ocular toxicity dose dependent- increased efficacy normal dose less often

Treatment aTB

47yr old Black African, HD, sm+ PTB, dry wt 68kgManagement?

Not on open HD unit!Medication:

Rifater 6 dailyEthambutol 600mg daily

Renal Disease - TreatmentCKD Stage 1 normal function but structural abnormalityCKD Stage 2 Cr Cl 60-90mls/min; Stage 3 30-60mls/min; Stage 4 15-30mls.min; Stage 5 <15mls/min.

• DoseDo not reduce dose as leads to lower peak dose

- Iso, Rif, – normal doses; Give piridoxine- PZA & E – normal doses for stages 1-3;

increased dose intervals in stages 4 & 5 CKD and HD; - Moxi – normal dose stages 1-3 & Tx; not suitable 3x/wk

Renal Disease - Treatment

• When?- H & R daily or 3x/wk- E & Z daily for stages 1-3, otherwise 3x/week; E peak & trough levels- Z signif removed by dialysis- 4-6hrs before haemodialysis or immediately after- Moxi daily 1-3 & Tx; not 3x/week

Peritoneal dialysis? – careful monitoring

Renal Disease - Treatment

• DurationStandard 6/12 for fully sensitiveCNS – 1 year

• ImmunosuppressionRif interferes with most regimens.Monitor levelsDouble steroid dosesMMF, ciclosporin and tacrolimus dosages

need adjustment

Drug recommendations…active TB

• Standard chemotherapy agents, standard duration as per NICE guidelines

• Monitor peak & trough levels - Ethambutol and aminoglycosides. Concern about over-and under-dosing.

• CKD stage 4-5 or haemodialysis – increase dosing intervals to 3 times weekly for E, Z & aminoglycosides. Reduces risk of drug accumulation and toxicity

BTS Guidelines Thorax 2010

TB in CKD - Summary

• High risk of TB – partic non-UK born, EMGs• Screen pre-tx & those at particular risk• Usual chemoprophylaxis• aTB – extra-pulmonary, low index of suspicion• Medication – do not reduce dose but inc dosing interval (E, Z,

aminoglycosides Stages 4-5 & haemodialysis)• Increased risk drug resistance • Drug interactions - Rif• Drug monitoring• VIGILANCE!

» BTS Guidelines Thorax 2010

Renal Impairment & TB:Unanswered Questions

What are the rates of TB and LTBI in countries with low background rate?

• What is the increased risk?How do the IgRA tests perform?When to screen for LTBI?Which patients should receive chemoprophylaxis?Dosages, dose intervals, timing on HD?Pharmacokinetics for patients on peritoneal dialysis?